Method of use of (imidazol-5-yl)methyl-2-quinolinone derivatives to inhibit smooth muscle cell proliferation

ABSTRACT

This invention comprises the use of compounds of formula (I)  
                 
 
     wherein the dotted line represents an optional bond; X is oxygen or sulfur; R 1  is hydrogen, C 1-12 alkyl, Ar 1 , Ar 2 C 1-6 alkyl, quinolinylC 1-6 alkyl, pyridylC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyl, aminoC 1-6 alkyl, or a radical of formula -Alk 1 -C(═O)—R 9 , -Alk 1 -S(O)—R 9  or -Alk 1 -S(O) 2 —R 9 ; R 2 , R 3  and R 16  each independently are hydrogen, hydroxy, halo, cyano, C 1-6 alkyl, C 1-6 alkyloxy, hydroxyC 1-6 alkyloxy, C 1-6 alkyloxy C 1-6 alkyloxy, aminoC 1-6 alkyloxy, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyloxy, Ar 1 , Ar 2 C 1-6 alkyl, Ar 2 oxy, Ar 2 C 1-6 alkyloxy, hydroxycarbonyl, C 1-6 alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C 2-6 alkenyl; R 4  and R 5  each independently are hydrogen, halo, Ar 1 , C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl , C 1-6 alkyloxy, C 1-6 alkylthio, amino, hydroxycarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylS(O)C 1-6 alkyl or C 1-6 alkylS(O) 2 C 1-6 alkyl; R 6  and R 7  each independently are hydrogen, halo, cyano, C 1-6 alkyl, 4,4-dimethyl-oxazolyl, C 1-6 alkyloxy or Ar 2 oxy; R 8  is hydrogen, C 1-6 alkyl, cyano, hydroxycarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonylC 1-6 alkyl, cyanoC 1-6 alkyl, C 1-6 alkyloxycarbonylC 1-6 alkyl, carboxyC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyl, imidazolyl, haloC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, aminocarbonylC 1-6 alkyl, or a radical of formula —O—R 10 , —S—R 10 , —N—R 11 R 12 ; R 17  is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkyloxycarbonyl, Ar 1 ; R 18  is hydrogen, C 1-6 alkyl, C 1-6 alkyloxy or halo; R 19  is hydrogen or C 1-6 alkyl; for the manufacture of a medicament to inhibit smooth muscle cell proliferation.

[0001] The present invention is concerned with a method of use ofcompounds of formula (I) for the inhibition of smooth muscle cellproliferation.

[0002] Proliferation of smooth muscle cells of the arterial wall inresponse to local injury is an important aetiologic factor of vascularproliferative disorders such as atherosclerosis and restenosis afterangioplasty. The incidence of restenosis after percutaneous transluminalcoronary angioplasty (PTCA) has been reported to be as high as 45%within three to six months after PTCA treatment (Indolfi et al., Naturemedicine, 1, 541-545 (1995)). Hence, compounds that inhibit smoothmuscle cell proliferation can be very useful to prevent or treatvascular proliferative disorders such as atherosclerosis and restenosis.

[0003] Heparin is a well known compound to inhibit proliferation ofsmooth muscle cells after coronary angioplasty (Buchwald et al., J.Cardiovasc. Pharmacol., 28, 481-487 (1996)).

[0004] In our co-pending application PCT/EP96/04515, published on Jun.19, 1997 as WO-97/21701, the compounds of formula (I), their preparationand compositions containing them are disclosed as farnesyl transferaseinhibitors useful for the treatment of ras dependent tumors.

[0005] Unexpectedly, it has been found that the compounds of formula (I)can be used to inhibit smooth muscle cell proliferation. Consequently,the present invention relates to a method of use of compounds of formula(I) for treating vascular proliferative disorders in a warm-bloodedanimal.

[0006] The present invention relates to a method of use of compounds offormula (I)

[0007] the pharmaceutically acceptable acid or base addition salts andthe stereochemically isomeric forms thereof, wherein

[0008] the dotted line represents an optional bond;

[0009] X is oxygen or sulfur;

[0010] R¹ is hydrogen, C₁₋₁₂alkyl, Ar¹, Ar²C₁₋₆alkyl,quinolinylC₁₋₆alkyl, pyridylC₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl,aminoC₁₋₆alkyl,

[0011] or a radical of formula -Alk¹-C(═O)—R⁹, -Alk¹-S(O)—R⁹ or-Alk¹-S(O)₂—R⁹,

[0012] wherein Alk¹ is C₁₋₆alkanediyl,

[0013] R⁹ is hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, amino, C₁₋₈alkylamino orC₁₋₈alkylamino substituted with C₁₋₆alkyloxycarbonyl;

[0014] R², R³ and R¹⁶ each independently are hydrogen, hydroxy, halo,cyano, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkyloxy, aminoC₁₋₆alkyloxy, mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹, Ar²C₁₋₆alkyl, Ar²oxy,Ar²C₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, trihalomethyl,trihalomethoxy, C₂₋₆alkenyl, 4,4-dimethyloxazolyl; or

[0015] when on adjacent positions R² and R³ taken together may form abivalent radical of formula

—O—CH₂—O—  (a-1),

—O—CH₂—CH₂—O—  (a-2),

—O—CH═CH—  (a-3),

—O—CH₂—CH₂—  (a-4),

—O—CH₂—CH₂—CH₂—  (a-5), or

—CH═CH—CH═CH—  (a-6);

[0016] R⁴ and R⁵ each independently are hydrogen, halo, Ar¹, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl , C₁₋₆alkyloxy, C₁₋₆alkylthio,amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl;

[0017] R⁶ and R⁷ each independently are hydrogen, halo, cyano,C₁₋₆alkyl, C₁₋₆alkyloxy, Ar²oxy, trihalomethyl, C₁₋₆alkylthio,di(C₁₋₆alkyl)amino, or

[0018] when on adjacent positions R⁶ and R⁷ taken together may form abivalent radical of formula

—O—CH₂—O—  (c-1), or

—CH═CH—CH═CH—  (c-2);

[0019] R⁸ is hydrogen, C₁₋₆alkyl, cyano, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, imidazolyl,haloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, or aradical of formula

—O—R¹⁰  (b-1),

—S—R¹⁰  (b-2),

—N—R¹¹R¹²  (b-3),

[0020] wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹,Ar²C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical or formula-Alk²-OR¹³ or -Alk²-NR¹⁴R¹⁵;

[0021] R¹¹ is hydrogen, C₁₋₁₂alkyl, Ar¹ or Ar²C₁₋₆alkyl;

[0022] R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylaminocarbonyl, Ar¹, Ar²C₁₋₆alkyl,C₁₋₆alkylcarbonylC₁₋₆alkyl, a natural amino acid. Ar¹carbonyl,Ar²C₁₋₆alkylcarbonyl, aminocarbonylcarbonyl,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy, aminocarbonyl,di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino, C₁₋₆alkylamino,C₁₋₆alkylcarbonylamino, or a radical or formula -Alk²-OR¹³ or-Alk²—NR¹⁴R¹⁵;

[0023] wherein Alk² is C₁₋₆alkanediyl;

[0024] R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl,Ar¹ or Ar²C₁₋₆alkyl;

[0025] R¹⁴ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl;

[0026] R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹ orAr²C₁₋₆alkyl;

[0027] R¹⁷ is hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,Ar¹;

[0028] R¹⁸ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo;

[0029] R¹⁹ is hydrogen or C₁₋₆alkyl;

[0030] Ar¹ is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy,amino, C₁₋₆alkyloxy or halo; and

[0031] Ar² is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy,amino, C₁₋₆alkyloxy or halo; for the inhibition of smooth muscle cellproliferation.

[0032] R⁴ or R⁵ may also be bound to one of the nitrogen atoms in theimidazole ring. In that case the hydrogen on the nitrogen is replaced byR⁴ or R⁵ and the meaning of R⁴ and R⁵ when bound to the nitrogen islimited to hydrogen, Ar¹, C₁₋₆alkyl, hydroxy-C₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl,C₁₋₆alkylS(O)₂C₁₋₆alkyl.

[0033] As used in the foregoing definitions and hereinafter halo definesfluoro, chloro, bromo and iodo; C₁₋₆alkyl defines straight and branchedchained saturated hydrocarbon radicals having from 1 to 6 carbon atomssuch as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl andthe like; C₁₋₈alkyl encompasses the straight and branched chainedsaturated hydrocarbon radicals as defined in C₁₋₆alkyl as well as thehigher homologues thereof containing 7 or 8 carbon atoms such as, forExample heptyl or octyl; C₁₋₁₂alkyl again encompasses C₁₋₈alkyl and thehigher homologues thereof containing 9 to 12 carbon atoms, such as, forexample, nonyl, decyl, undecyl, dodecyl; C₁₋₆alkyl again encompassesC₁₋₁₂alkyl and the higher homologues thereof containing 13 to 16 carbonatoms, such as, for example, tridecyl, tetradecyl, pentedecyl andhexadecyl; C₂₋₆alkenyl defines straight and branched chain hydrocarbonradicals containing one double bond and having from 2 to 6 carbon atomssuch as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 3-methyl-2-butenyl, and the like; C₁₋₆alkanediyl definesbivalent straight and branched chained saturated hydrocarbon radicalshaving from 1 to 6 carbon atoms, such as, for example, methylene,1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl,1,6-hexanediyl and the branched isomers thereof. The term “C(═O)” refersto a carbonyl group, “S(O)” refers to a sulfoxide and “S(O)₂” to asulfon. The term “natural amino acid” refers to a natural amino acidthat is bound via a covalent amide linkage formed by loss of a moleculeof water between the carboxyl group of the amino acid and the aminogroup of the remainder of the molecule. Example s of natural amino acidsare glycine, alanine, valine, leucine, isoleucine, methionine, proline,phenylanaline, tryptophan, serine, threonine, cysteine, tyrosine,asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine,histidine.

[0034] The pharmaceutically acceptable acid or base addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid and non-toxic base addition salt forms which thecompounds of formula (I) are able to form. The compounds of formula (I)which have basic properties can be converted in their pharmaceuticallyacceptable acid addition salts by treating said base form with anappropriate acid. Appropriate acids comprise, for example, inorganicacids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid;sulfuric; nitric; phosphoric and the like acids; or organic acids suchas, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic,oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric,malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

[0035] The compounds of formula (I) which have acidic properties may beconverted in their pharmaceutically acceptable base addition salts bytreating said acid form with a suitable organic or inorganic base.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts. e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, andsalts with amino acids such as, for example, arginine, lysine and thelike.

[0036] The terms acid or base addition salt also comprise the hydratesand the solvent addition forms which the compounds of formula (I) areable to form. Example s of such forms are e.g. hydrates, alcoholates andthe like.

[0037] The term stereochemically isomeric forms of compounds of formula(I), as used hereinbefore, defines all possible compounds made up of thesame atoms bonded by the same sequence of bonds but having differentthree-dimensional structures which are not interchangeable, which thecompounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of a compound encompasses themixture of all possible stereochemically isomeric forms which saidcompound may possess. Said mixture may contain all diastereomers and/orenantiomers of the basic molecular structure of said compound. Allstereochemically isomeric forms of the compounds of formula (I) both inpure form or in admixture with each other are intended to be embracedwithin the scope of the present invention.

[0038] Some of the compounds of formula (I) may also exist in theirtautomeric forms. Such forms although not explicitly indicated in theabove formula are intended to be included within the scope of thepresent invention.

[0039] Whenever used hereinafter, the term “compounds of formula (I)” ismeant to include also the pharmaceutically acceptable acid or baseaddition salts and all stereoisomeric forms.

[0040] Preferably the substituent R¹⁸ is situated on the 5 or 7 positionof the quinolinone moiety and substituent R¹⁹ is situated on the 8position when R¹⁸ is on the 7-position.

[0041] Interesting compounds are these compounds of formula (I) whereinX is oxygen.

[0042] Also interesting compounds are these compounds of formula (I)wherein the dotted line represents a bond, so as to form a double bond.

[0043] Another group of interesting compounds are those compounds offormula (I) wherein R¹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,di(C₁₋₆alkyl)aminoC₁₋₆alkyl, or a radical of formula -Alk¹-C(═O)—R⁹,wherein Alk¹ is methylene and R⁹ is C₁₋₈alkylamino substituted withC₁₋₆alkyloxycarbonyl.

[0044] Still another group of interesting compounds are those compoundsof formula (I) wherein R³ is hydrogen or halo: and R² is halo,C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkyloxy, trihalomethoxy orhydroxyC₁₋₆alkyloxy.

[0045] A further group of interesting compounds are those compounds offormula (I) wherein R² and R³ are on adjacent positions and takentogether to form a bivalent radical of formula (a-1), (a-2) or (a-3).

[0046] A still further group of interesting compounds are thosecompounds of formula (I) wherein R⁵ is hydrogen and R⁴ is hydrogen orC₁₋₆alkyl.

[0047] Yet another group of interesting compounds are those compounds offormula (I) wherein R⁷ is hydrogen; and R⁶ is C₁₋₆alkyl or halo,preferably chloro, especially 4-chloro.

[0048] A particular group of compounds are those compounds of formula(I) wherein R⁸ is hydrogen, hydroxy, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, imidazolyl, or a radicalof formula —NR¹¹R¹² wherein R¹¹ is hydrogen or C₁₋₁₂alkyl and R¹² ishydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxy,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, or a radical of formula -Alk²-OR¹³wherein R¹³ is hydrogen or C₁₋₆alkyl.

[0049] Prefered compounds are those compounds wherein R¹ is hydrogen,C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl, or aradical of formula -Alk¹-C(═O)—R⁹, wherein Alk¹ is methylene and R⁹ isC₁₋₈alkylamino substituted with C₁₋₆alkyloxycarbonyl; R² is halo,C₁₋₆alkyl, C₂₋ ₆alkenyl, C₁₋₆alkyloxy, trihalomethoxy,hydroxyC₁₋₆alkyloxy or Ar¹; R³ is hydrogen; R⁴ is methyl bound to thenitrogen in 3-position of the imidazole; R⁵ is hydrogen; R⁶ is chloro;R⁷ is hydrogen; R⁸ is hydrogen, hydroxy, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl,imidazolyl, or a radical of formula —NR¹¹R¹² wherein R¹¹ is hydrogen orC₁₋₁₂alkyl and R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, or a radical of formula -Alk²-OR¹³wherein R¹³ is C₁₋₆alkyl; R¹⁷ is hydrogen and R¹⁸ is hydrogen.

[0050] Most preferred compounds are

[0051]4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2( 1H)-quinolinone,

[0052]6-[amino(4-chlorophenyl)-1-methyl-1H-imidazol-5-ylmethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;

[0053]6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone;

[0054]6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinonemonohydrochloride.monohydrate;

[0055]6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone,

[0056] 6-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-(3-propylphenyl)-2(1H)-quinolinone; a stereoisomeric form thereof or a pharmaceuticallyacceptable acid or base addition salt; and

[0057](+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;or a pharmaceutically acceptable acid addition salt thereof.

[0058] The compounds of formula (I), wherein X is oxygen, said compoundsbeing represented by formula (I-a), may be prepared by hydrolysing anintermediate ether of formula (II), wherein R is C₁₋₆alkyl, according toart-known methods, such as stirring the intermediate of formula (II) inan aqueous acid solution. An appropriate acid is for instancehydrochloric acid. Subsequently the resulting quinolinone wherein R¹ ishydrogen may be transformed into a quinolinone, wherein R¹ has a meaningas defined hereinabove apart from hydrogen, by art-known N-alkylation.

[0059] The compounds of formula (I), wherein R⁸ is hydroxy, saidcompounds being referred to as compounds of formula (I-b) may beprepared by reacting an intermediate ketone of formula (III) with aintermediate of formula (IV-a), wherein P is an optional protectivegroup such as, for example, a sulfonyl group, e.g. a dimethylaminosulfonyl group, which can be removed after the addition reaction. Saidreaction requires the presence of a suitable strong base, such as, forexample, butyl lithium in an appropriate solvent, such as, for example,tetrahydrofuran and the presence an appropriate silanederivative, suchas, for example, triethylchlorosilane. During the work-up procedure anintermediate silane derivative is hydrolyzed. Other procedures withprotective groups analogous to silanederivatives can also be applied.

[0060] Compounds of formula (I-b-1), being compounds of formula (I-b)wherein the dotted line is a bond and R¹ is hydrogen, can be prepared byreacting an intermediate of formula (XXI) with an intermediate offormula (IV-a), as described hereinabove for the synthesis of compoundsof formula (I-b). The thus obtained intermediate of formula (XXII)undergoes ring opening of the isoxazole moiety by stirring it with anacid, such as, e.g. TiCl₃, in the presence of water. Subsequenttreatment of an intermediate of formula (XXIII) with a suitable reagentsuch as, e.g. R¹⁷CH₂COCl or R¹⁷CH₂COOC₂H₅, yields either directly acompound of formula (I-b-1) or an intermediate which can be converted toa compound of formula (I-b-1) by treatment with a base such as, e.g.potassium tert-butoxide.

[0061] Intermediates of formula (XXI) can conveniently be prepared bytreating an intermediate of formula (XVI), described hereinafter, underacidic conditions.

[0062] Compounds of formula (I) wherein R⁸ is a radical of formula—N—R¹¹R¹², said compounds being represented by formula (I-g) may beprepared by reacting an intermediate of formula (XIII), wherein W is anappropriate leaving group such as, for example, halo, with a reagent offormula (XIV). Said reaction may be performed by stirring the reactantsin an appropriate solvent such as, for example, tetrahydrofuran.

[0063] The compounds of formula (I) may also be prepared by convertingcompounds of formula (I) into other compounds of formula (I).

[0064] Compounds wherein the dotted line represents a bond can beconverted into compounds wherein the dotted line does not represent abond, by art-known hydrogenation methods. Vice versa. compounds whereinthe dotted line does not represent a bond may be converted intocompounds wherein the dotted line represents a bond by art-knownoxidation reactions.

[0065] Compounds of formula (I) wherein R⁸ is hydroxy, said compoundsbeing represented by formula (I-b) may be converted into compounds offormula (I-c), wherein R^(8a) has the meaning of R¹⁰ except forhydrogen, by art-know O-alkylation or O-acylation reactions; such as,for instance, reacting the compound of formula (I-b) with an alkylatingreagent such as R^(8a)-W in appropriate conditions, such as, forexample, a dipolar aprotic solvent, e.g. DMF, in the presence of a base,e.g. sodium hydride. W is a suitable leaving group, such as, forexample. halo or a sulfonylgroup.

[0066] As an alternative to the above reaction procedure, compounds offormula (I-c) may also be prepared by reacting an intermediate offormula (I-b) with a reagent of formula R^(8a)—OH in acidic medium.

[0067] Compounds of formula (I-b) may also be converted into compoundsof formula (I-g), wherein R¹¹ is hydrogen and R¹² is C₁₋₁₆alkylcarbonyl,by reacting compounds of formula (I-b) in acidic medium, such assulfuric acid, with C₁₋₁₆alkyl-CN in a Ritter type reaction. Further,compounds of formula (I-b) may also be converted into compounds offormula (I-g), wherein R¹¹ and R¹² are hydrogen, by reacting compounds(I-b) with ammonium acetate and subsequent treatment with NH₃ (aq.).

[0068] Compounds of formula (I-b) may also be converted into compoundsof formula (I-d), wherein R⁸ is hydrogen, by submitting the compounds offormula (I-b) to appropriate reducing conditions, such as, stirring intrifluoroacetic acid in the presence of an appropriate reducing agent,such as sodium borohydride or alternatively stirring the compounds offormula (I-b) in acetic acid in the presence of formamide. Furthermore,compounds of formula (I-d) wherein R⁸ is hydrogen may be converted intocompounds of formula (I-e) wherein R^(8b) is C₁₋₆alkyl by reactingcompounds of formula (I-d) with a reagent of formula (V) in anappropriate solvent, such as, for instance, diglyme in the presence of abase such as, for example, potassium butoxide.

[0069] A compound of formula (I-f), defined as a compound of formula (I)wherein X is sulfur may be prepared by reacting the correspondingcompound of formula (I-a), with a reagent like phosphorus pentasulfideor Lawesson's reagent in a suitable solvent such as, for example,pyridine.

[0070] Compounds of formula of formula (I), wherein R¹ is hydrogen and Xis oxygen, said compounds being defined as compounds of formula (I-a-1 )may be prepared by reacting a nitrone of formula (VI) with the anhydrideof a carboxylic acid, such as, for example, acetic anhydride, thusforming the corresponding ester on the 2 position of the quinolinemoiety. Said quinoline ester can be hydrolyzed in situ to thecorresponding quinolinone using a base such as, for example, potassiumcarbonate.

[0071] Alternatively, compounds of formula (I-a-1 ) can be prepared byreacting a nitrone of formula (VI) with a sulfonyl containingelectrophilic reagent such as, for example, p-toluenesulfonylchloride inthe presence of a base such as, for example, aqueous potassiumcarbonate. The reaction initially involves the formation of a2-hydroxy-quinoline derivative which is subsequently tautomerized to thedesired quinolinone derivative. The application of art-known conditionsof phase transfer catalysis may, enhance the rate of the reaction.

[0072] Compounds of formula (I-a-1 ) may also be prepared by anintramolecular photochemical rearrangement of compounds of formula (VI).Said rearrangement can be carried out by dissolving the reagents in areaction-inert solvent and irradiating at a wavelength of 366 nm. It isadvantageous to use degassed solutions and to conduct the reaction underan inert atmosphere such as, for example, oxygen free argon or nitrogengas, in order to minimize undesired side reactions or reduction ofquantum yield.

[0073] The compounds of formula (I) may also be converted into eachother via art-known reactions or functional group transformations. Anumber of such transformations are already described hereinabove. Otherexamples are hydrolysis of carboxylic esters to the correspondingcarboxylic acid or alcohol; hydrolysis of amides to the correspondingcarboxylic acids or amines; hydrolysis of nitrites to the correspondingamides; amino groups on imidazole or phenyl may be replaced by ahydrogen by art-known diazotation reactions and subsequent replacementof the diazo-group by hydrogen; alcohols may be converted into estersand ethers; primary amines may be converted into secondary or tertiaryamines; double bonds may be hydrogenated to the corresponding singlebond.

[0074] Intermediates of formula (III) may be prepared by reacting aquinolinone derivative of formula (VIII) with an intermediate of formula(IX) or a functional derivative thereof under appropriate conditions,such as, for example, a strong acid, e.g. polyphosphoric acid in anappropriate solvent. The intermediate of formula (VIII) may be formed bycyclization of an intermediate of formula (VII) by stirring in thepresence of a strong acid, e.g. polyphosphoric acid. Optionally saidcyclization reaction may be followed by an oxidation step, which can beperformed by stirring the intermediate formed after cyclization in anappropriate solvent, such as, for example. a halogenated aromaticsolvent, e.g. bromobenzene, in the presence of a oxidizing agent, e.g.bromine or iodine. At this stage it may also be appropriate to changethe R¹ substituent by art-known functional group transformationreaction.

[0075] Intermediates of formula (III-a-1), being intermediates offormula (III) wherein the dotted line is a bond, R¹ and R¹⁷ are hydrogenand X is oxygen, can be prepared starting from an intermediate offormula (XVII), which is conveniently prepared by protecting thecorresponding ketone. Said intermediate of formula (XVII) is stirredwith an intermediate of formula (XVIII) in the presence of a base suchas sodium hydroxide, in an appropriate solvent, such as an alcohol, e.g.methanol. The thus obtained intermediate of formula (XVI) undergoeshydrolysis of the ketal and ring opening of the isoxazole moiety bystirring the intermediate of formula (XVI) with an acid, such as forexample, TiCl₃, in the presence of water. Subsequently acetic anhydrideis used to prepare an intermediate of formula (XV), which undergoes ringclosure in the presence of a base such as, for example, potassiumtert-butoxide.

[0076] Intermediates of formula (III-a-1 ) can easily be converted tointermediates of formula (III-a), defined as intermediates of formula(III) wherein the dotted line represents a bond, X is oxygen, R¹⁷ ishydrogen and R¹ is other than hydrogen, using art-known N-alkylationprocedures.

[0077] An alternative way to prepare intermediates of formula (III-a-1), wherein X is oxygen and R¹ is hydrogen, starts from an intermediateof formula (XVI), which is conveniently converted to intermediates offormula (XIX) using catalytic hydrogenation conditions, e.g. by usinghydrogen gas and palladium on carbon in a reaction-inert solvent suchas, e.g. tetrahydrofuran. Intermediates of formula (XIX) are convertedto intermediates of formula (XX) by submitting intermediates (XIX) to anacetylation reaction, e.g. by treatment with the anhydride of acarboxylic acid, e.g. acetic anhydride in a reaction-inert solvent, e.g.toluene, and subsequent treatment with a base such as, e.g. potassiumtert-butoxide in a reaction-inert solvent, e.g. 1,2-dimethoxyethane.Intermediates of formula (III-a-1 ) can be obtained by treatingintermediates of formula (XX) in acidic conditions.

[0078] Intermediates of formula (II) may be prepared by reacting anintermediate of formula (X), wherein W is an appropriate leaving group,such as, for example, halo, with an intermediate ketone of formula (XI).This reaction is performed by converting the intermediate of formula (X)into a organometallic compound, by stirring it with a strong base suchas butyl lithium and subsequently adding the intermediate ketone offormula (XI). Although this reaction gives at first instance a hydroxyderivative (i.e. R⁸ is hydroxy), said hydroxy derivative can beconverted into other intermediates wherein R⁸ has another definition byperforming art-known (functional group) transformations.

[0079] The intermediate nitrones of formula (VI) may be prepared byN-oxidizing quinoline derivatives of formula (XII) with an appropriateoxidizing agent such as, for example, m-chloro-peroxybenzoic acid orH₂O₂ in an appropriate solvent such as. for example, dichloromethane.

[0080] Said N-oxidation may also be carried out on a precursor of aquinoline of formula (XII).

[0081] The intermediates of formula (XII) are supposed to be metabolizedin vivo into compounds of formula (I) via intermediates of formula (VI).Hence, intermediates of formula (XII) and (VI) may act as prodrugs ofcompounds of formula (I).

[0082] The compounds of formula (I) and some of the intermediates haveat least one stereogenic center in their structure. This stereogeniccenter may be present in a R or a S configuration.

[0083] The compounds of formula (I) as prepared in the hereinabovedescribed processes are generally racemic mixtures of enantiomers whichcan be separated from one another following art-known resolutionprocedures. The racemic compounds of formula (I) may be converted intothe corresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

[0084] This invention provides a method of use of compounds of formula(I) to inhibit the proliferation of smooth muscle cells, as illustratedby pharmacological Example C. 1.

[0085] Hence, the compounds of formula (I) can be used for themanufacture of a medicament for the inhibition of smooth muscle cellproliferation and consequently the use for the manufacture of amedicament for the treatment of vascular proliferative disorders such asatherosclerosis and restenosis is also provided.

[0086] It has been proposed in literature that the mechanism behindsmooth muscle cell proliferation involves the loss of normal regulationof cellular growth, a process wherein ras proteins plays a significantrole. Accordingly, it has been suggested that compounds having farnesyltransferase inhibiting properties, can be useful to prevent smoothmuscle cell proliferation after vascular injury (Indolfi et al., Naturemedicine, 1, 541-545 (1995) and Irani et al., Biochemical aidbiophysical research Commmunications, 202, 1252-1258, (1994)).

[0087] Atherosclerosis is a disorder characterized by the deposition offatty substances in and fibrosis of the inner layer of the arteries.

[0088] Restenosis is the narrowing of tubular passageways of a subjectafter the tubular walls have been traumatized. This can be caused byuncontrolled cellular proliferation of neointimal tissue which often isa complication due to the use of revascularization techniques such as,e.g. saphenous vein bypass grafting, endarterectomy, percutaneoustransluminal coronary angioplasty (PTCA) and the like. Restenosis refersto a worsening or recurrence of lumenal stenosis in an artery which ischaracterized by a hyperplasia of cells of the arterial wall. In thisrespect, restenosis differs notably from an occlusion of the artery byan arterial atherosclerotic plaque or occlusion by thrombus.

[0089] Restenosis is not restricted or limited to the coronary arteries.It can also occur in for Example peripheral vascular systems.

[0090] Angioplasty is a technique whereby an artery clogged by anatherosclerotic plaque and/or thrombus is mechanically cleared. Such aclogged or blocked artery prevents adequate blood flow. Angioplastyprocedures are much less invasive and much less traumatic thanconventional alternatives such as coronary bypass surgery and havegained widespread acceptance as a means of obtaining dilation orclearance of arteries. In conventional angioplasty procedures, a smallballoon-tipped catheter is introduced into an artery, often using aguide wire or a catheter tube in which a collapsed balloon may bepositioned at one more points of arterial stenosis, i.e. narrowing. Oncepositioned within the blockage, the balloon is inflated, therebystretching and/or fracturing the blockage and enlarging the lumen(opening) of the artery. After the balloon is deflated and removed fromthe artery, the artery's internal diameter is generally larger,resulting in restoration of blood flow. These balloon and catheterassemblies are often referred to as coronary balloon dilation catheters.However, said angioplasty procedures involve risk of both local andsystemic thromboembolic effects, tearing of an arterial wall andrestenosis.

[0091] Restenosis after balloon angioplasty is also referred to as‘percutaneous transluminal coronary angioplasty restenosis’ and ischaracterized by the return of blockage in the artery due to neointimalformation of a layer of smooth muscle cells in the intima after ballooninjury.

[0092] Accordingly, the present invention provides a method of treatingvascular proliferative disorders in a warm-blooded animal, such asatherosclerosis or restenosis. which comprises administering to saidwarm-blooded animal a prophylactically or therapeutically effectiveamount of a compound of formula (I).

[0093] The present invention provides further a method of inhibitingsmooth muscle cell proliferation in a warm-blooded animal whichcomprises administering to said warm-blooded animal a prophylacticallyor therapeutically effective amount of a compound of formula (I).

[0094] Balloon angioplasty can be followed by a mechanical/surgicalprocedure known as intravascular stenting, a procedure in which anexpandable metallic sleeve, or scaffold, i.e. a stent, is placed withinthe artery after angioplasty. However, after the insertion of the stenta disorder known as ‘coronary artery stent restenosis’ can occur wherebythe blockage in the artery returns due to neointimal formation of alayer of smooth muscle cells in the intima. Therefore, it may beadvantageous to cover or coat said stent with a coating material whichcomprises a compounds of formula (I) in order to inhibit smooth musclecell proliferation. Hence, in an aspect, this invention also providesstents covered or coated with a coating material which comprises anamount of a compound of formula (I) effective in preventing, treating orreducing smooth muscle cell proliferation. Commercially available stentsare e.g. balloon expandable stents such as, e.g. Palmaz-Schatz™ stent,Strecker™ stent and Gianturco-Roubin™ stent, and self expandable stentssuch as, e.g. Gianturco™ expandable wire stent and Wallstent™, otherstents are Palmaz-Schatz Crown™, Cross-Flex™, ACS Multi-Link™, Nir™,Micro Stent II™ and Wiktor™.

[0095] In a way, the invention also relates to catheters, or othertransluminal devices coated or covered with a coating material whichcomprises an amount of a compound of formula (I) effective inpreventing, treating or reducing smooth muscle cell proliferation.

[0096] The metallic surface of a stent can be coated in a number ofways. The surface can be prepared by a two-step procedure includingcovalently linking an organosilane having amine reactive sites, with thesurface of the metallic member, typically through a metal oxide thereof.Also, an organosilane having a vinyl functionality pendant from thesurface can be used. Thereafter, a biocompatible coating material can becovalently linked to the organosilane coating.

[0097] The coating layer comprising an amount of a compound of formula(I) may also be applied as a mixture of a polymeric precursor and acompound of formula (I) which is finely divided or dissolved in apolymer solvent or vehicle which is thereafter cured in situ.

[0098] The coating may be applied by dipping or spraying usingevaporative solvent materials of relatively high vapor pressure toproduce the desired viscosity and coating thickness. The coating furtheris one which adheringly conforms to the surface of the filaments of theopen structure of the stent so that the open lattice nature of thestructure of the braid or other pattern is preserved in the coateddevice.

[0099] The major constituent of the stent coating should haveelastomeric properties. The stent coating is preferably a suitablehydrophobic biostable elastomeric material which does not degrade andwhich minimizes tissue rejection and tissue inflammation and one whichwill undergo encapsulation by tissue adjacent the stent implantationsite. Polymers suitable for such coatings include silicones (e.g.polysiloxanes and substituted polysiloxanes), polyurethanes,thermoplastic elastomers in general, ethylene vinyl acetate copolymers,polyolefin elastomers, and EPDM rubbers.

[0100] The loading of the stent coating with the compound of formula (I)may vary. The desired release rate profile can be tailored by varyingthe coating thickness, the radial distribution, the mixing method, theamount of said compound of formula (I), and the crosslink density of thepolymeric material.

[0101] Methods for coating stents are described in, e.g. WO-96/32907,U.S. Pat. No. 5,607,475, U.S. Pat. No. 5,356,433, U.S. Pat. No.5,213,898, U.S. Pat. No. 5,049403, U.S. Pat. No. 4,807,784 and U.S. Pat.No. 4,565,740.

[0102] Stents are made of a biocompatible material such as, e.g.stainless steel, tantalum, titanium, nitinol, gold, platinum, inconel,iridium, silver, tungsten, or another biocompatible metal, or alloys ofany of these. Stainless steel and tantalum are particularly useful. Saidstent can be covered by one or more layers of a biocompatible coatingmaterial such as, e.g. carbon, carbon fiber, cellulose acetate,cellulose nitrate, silicone, parylene, parylene derivatives,polyethylene teraphthalate, polyurethane, polyamide, polyester,polyorthoester, polyanhydride, polyether sulfone, polycarbonate,polypropylene, high molecular weight polyethylene,polytetrafluoroethylene, or another biocompatible material, or mixtureor copolymers of these. Parylene is both a generic name for a knowngroup of polymers based on p-xylene and made by vapor phasepolymerization, and a name for the unsubstituted one of such polymers.Said one or more layers of biocompatible material comprise a compound offormula (I) of the present invention and advantageously provide acontrolled release of said compound of formula (I) effective inpreventing, treating or reducing smooth muscle cell proliferation. Saidone or more layers of biocompatible material can further comprisebioactive materials such as, e.g. heparin or another thrombin inhibitor,hirudin, hirulog, argatroban, D-phenylalanyl-L-poly-L-arginylchloromethyl ketone, or another antithrombogenic agent, or mixturesthereof; urokinase, streptokinase, a tissue plasminogen activator, oranother thrombolytic agent, or mixtures thereof; a fibrinolytic agent: avasospasm inhibitor; a calcium channel blocker, a nitrate, nitric oxide,a nitric oxide promoter or another vasodilator; an antimicrobial agentor antibiotic; aspirin, ticlopdine, a glycoprotein IIb/IIIa inhibitor oranother inhibitor of surface glycoprotein receptors, or anotherantiplatelet agent; colchicine or another antimitotic, or anothermicrotubule inhibitor; a retinoid or another antisecretory agent;cytochalasin or another actin inhibitor; deoxyribonucleic acid, anantisense nucleotide or another agent for molecular geneticintervention; methotrexate or another antimetabolite orantiproliferative agent; an anticancer chemotherapeutic agent;dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate oranother dexamethasone derivative, or another anti-inflammatory steroidor non-steroidal antiinflammatory agent: cyclosporin or anotherimmunosuppressive agent; trapidal (a PDGF antagonist), angiopeptin (agrowth hormone antagonist), an anti-growth factor antibody, or anothergrowth factor antagonist; dopamine, bromocriptine mesylate, pergolidemesylate or another dopamine agonist: captopril, enalApril or anotherangiotensin converting enzyme (ACE) inhibitor; ascorbic acid,alphatocopherol, superoxide dismutase, deferoxamine, a 21-aminosteroid(lasaroid) or another free radical scavenger; or a mixture of any ofthese.

[0103] Hence, the present invention further provides a method oftreating vascular proliferative disorders in a warm-blooded animal, suchas percutaneous transluminal coronary angioplasty restenosis or coronaryartery stent restenosis, which comprises administering to saidwarm-blooded animal a prophylactically or therapeutically effectiveamount of a compound of formula (I).

[0104] In particular said warm-blooded animal is a mammal or morespecifically a human.

[0105] As is known to those skilled in the art, a prophylactically ortherapeutically effective amount varies with the type of therapeuticagent. It is known to those skilled in the art how to determine aprophylactically or therapeutically effective amount of a suitabletherapeutic agent.

[0106] In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes. To prepare the pharmaceutical compositions ofthis invention, an effective amount of a particular compound, in base oracid addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for administration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols and the like in the case oforal liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, to aid solubility for example, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. In the compositions suitable for percutaneous administration,the carrier optionally comprises a penetration enhancing agent and/or asuitable wetting agent, optionally combined with suitable additives ofany nature in minor proportions, which additives do not cause asignificant deleterious effect to the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. It is especially advantageous to formulate theaforementioned pharmaceutical compositions in dosage unit form for easeof administration and uniformity of dosage. Dosage unit form as used inthe specification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Example s of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

[0107] Those skilled in the art could easily determine the effectiveamount from the test results presented hereinafter. In general it iscontemplated that an effective amount would be from 0.0001 mg/kg to 100mg/kg body weight, and in particular from 0.001 mg/kg to 10 mg/kg bodyweight. It may be appropriate to administer the required dose as two,three, four or more sub-doses at appropriate intervals throughout theday. Said sub-doses may be formulated as unit dosage forms, for example,containing 0.01 to 500 mg, and in particular 0.1 mg to 200 mg of activeingredient per unit dosage form.

[0108] Experimental Part

[0109] Hereinafter “THF” means tetrahydrofuran, “DIPE” meansdiusopropylether, “DCM” means dichloromethane, “DMF” meansN,N-dimethylformamide and “ACN” means acetonitrile. Of some compounds offormula (I) the absolute stereochemical configuration was notexperimentally determined. In those cases the stereochemically isomericform which was first isolated is designated as “A” and the second as“B”, without further reference to the actual stereochemicalconfiguration.

A. PREPARATION OF THE INTERMEDIATES Example A.1

[0110] 1a) N-Phenyl-3-(3-chlorophenyl)-2-propenamide (58.6 g) andpolyphosphoric acid (580 g) were stirred at 100° C. overnight. Theproduct was used without further purification, yielding quant.(±)-4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone (interm. 1-a).

[0111] 1b) Intermnediate (1-a) (58.6 g), 4-chlorobenzoic acid (71.2 g)and polyphosphoric acid (580 g) were stirred at 140° C. for 48 hours.The mixture was poured into ice water and filtered off. The precipitatewas washed with water, then with a diluted NH₄OH solution and taken upin DCM. The organic layer was dried, filtered off and evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 99/1/0.1). The pure fractions were collected andevaporated, and recrystallized from CH₂Cl₂/CH₃OH/DIPE, yielding 2.2g of(±)-6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone (interm. 1-b, mp. 194.8° C.).

[0112] 1c) Bromine (3.4 ml) in bromobenzene (80 ml) was added dropwiseat room temperature to a solution of intermediate (1-b) (26 g) inbromobenzene (250 ml) and the mixture was stirred at 160° C. overnight.The mixture was cooled to room temperature and basified with NH₄OH. Themixture was evaporated, the residue was taken up in ACN and filteredoff. The precipitate was washed with water and air dried, yielding 24 g(92.7%) of product. A sample was recrystallized from CH₂Cl₂/CH₃OH/DIPE,yielding 2.8 g of6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-2(1H)-quinolinone; mp. 234.8° C.(interm. 1-c).

[0113] 1d) Iodomethane (6.2 ml) was added to a mixture of intermediate(1-c) (20 g) and benzyltriethylammonium chloride (5.7 g) intetrahydrofuran (200 ml) and sodium hydroxide ( 10N) (200 ml) and themixture was stirred at room temperature overnight. ethyl acetate wasadded and the mixture was decanted. The organic layer was washed withwater, dried, filtered off and evaporated till dryness. The residue waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 99.75/0.25/0.1). The pure fractions were collectedand evaporated, yielding 12.3 g (75%) of6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methyl-2( 1H)-quinolinone; mp.154.7° C. (interm. 1-d).

[0114] In a similar way, but starting from intermediate (1-b),(±)-6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-3,4-dihydro-1-methyl-2(1H)-quinolinone (interm 1-e) was prepared.

Example A.2

[0115] Butyllithium in hexane (1.6 M) (12.75 ml) was added dropwise at−20° C. under N₂ to a solution of6-bromo-4-(3-chlorophenyl)-2-methoxyquinoline (6.7 g) in THF (60 ml) andthe mixture was stirred at −20° C. for 30 minutes. A solution of(1-butyl-1H-imidazol-5-yl)(4-chlorophenyl)methanone (3.35 g) intetrahydrofuran (30 ml) was added at −20° C. under N₂ and the mixturewas stirred at room temperature for one night. Water was added and themixture was extracted with ethyl acetate. The organic layer was dried,filtered off and evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1).The pure fractions were collected and evaporated, yielding 2.5 g (total48%) of(±)-α-(1-butyl-1H-imidazol-5-yl)-4-(3-chlorophenyl)-a-(4-chlorophenyl)-2-methoxy-6-quinoline-methanol(interm. 2).

Example A.3

[0116] 3a) Butyllithium (30.1 ml) was added slowly at −78° C. to asolution of N,N-dimethyl-1H-imidazol-1-sulfonamide (8,4 g) intetrahydrofuran (150 ml) and the mixture was stirred at −78° C. for 15minutes. Chlorotriethylsilane (8.1 ml) was added and the mixture wasstirred till the temperature reached 20° C. The mixture was cooled till−78° C., butyllithium (30.1 ml) was added, the mixture was stirred at−78° C. for 1 hour and allowed to reach −15° C. The mixture was cooledagain till −78° C., a solution of6-(4-chlorobenzoyl)-1-methyl-4-phenyl-2(1H)-quinolinone (15 g) intetrahydrofuran (30 ml) was added and the mixture was stirred till thetemperature reached 20° C. The mixture was hydrolized and extracted withethyl acetate. The organic layer was dried, filtered off and evaporatedtill dryness. The product was used without further purification,yielding 26 g (100%) of(±)-4-[(4-chlorophenyl)(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)hydroxymethyl]-N,N-dimethyl-2-(triethylsilyl)-1H-imidazole-1-sulfonamide(inter-m. 3-a).

[0117] A mixture of intermediate (3-a) (26 g) in sulfuric acid (2.5 ml)and water (250 ml) was stirred and heated at 110° C. for 2 hours. Themixture was poured into ice, basified with NH₄OH and extracted with DCM.The organic layer was dried, filtered off and evaporated till dryness.The residue was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH/NH₄OH 99/1/0.2). The pure fractions were collectedand evaporated, yielding 2.4 g (11%) of(±)-4-[(4-chlorophenyl)(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)hydroxymethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide(interm. 3-b).

Example A.4

[0118] Compound (3) (3 g) was added at room temperature to thionylchloride (25 ml). The mixture was stirred and refluxed at 40° C.overnight. The solvent was evaporated till dryness. The product was usedwithout further purification, yielding 3.49 g of(±)-4-(3-chlorophenyl)-1-methyl-6-[(1-(4-methylphenyl)-1-(4-methyl-4H-pyrrol-3-yl)ethyl]-2(1H)-quinolinonehydrochloride (interm. 4).

Example A.5

[0119] a) Toluene (1900 ml) was stirred in a round-bottom flask (5 l)using a water separator. (4-Chlorophenyl)(4-nitrophenyl)methanone (250g) was added portionwise. p-Toluene-sulfonic acid (54.5 g) was addedportionwise. Ethylene glycol (237.5 g) was poured out into the mixture.The mixture was stirred and refluxed for 48 hours. The solvent wasevaporated. The residue was dissolved into ethyl acetate (5 l) andwashed twice with a K₂CO₃ 10% solution. The organic layer was separated,dried, filtered and the solvent was evaporated. The residue was stirredin DIPE, filtered off and dried (vacuum, 40° C., 24 hours), yielding 265g (91%) of 2-(4-chlorophenyl)-2-(4-nitrophenyl)-1,3-dioxolane (interm.5-a).

[0120] b) Sodium hydroxide (16.4 g) and (3-methoxyphenyl)acetonitrile(20.6 ml) were added at room temperature to a solution of interm. (5-a)(25 g) in methanol (100 ml) and the mixture was stirred at roomtemperature overnight. Water was added, the precipitate was filteredoff, washed with cold methanol and dried. The product was used withoutfurther purification, yielding 30 g (90%) of5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-3-(3-(methoxyphenyl)-2,1-benzisoxazole(interm. 5-b).

[0121] c) Interm. (5-b) (30 g) in THF (250 ml) was hydrogenated withpalladium on carbon (3 g) as a catalyst at room temperature for 12 hoursunder a 2.6 10⁵ Pa pressure in a Parr apparatus. After uptake of H₂ (1equivalent), the catalyst was filtered through celite and the filtratewas evaporated till dryness. The product was used without furtherpurification, yielding 31.2 g (100%) of(3-methoxyphenyl)[2-amino-5-[2-(4-chloro-phenyl)-1,3-dioxolan-2-yl]phenyl]methanone(interm. 5-c).

[0122] d) Acetic anhydride (13.9 ml) was added to a solution of interm.(5-c) (31.2 g) in toluene (300 ml) and the mixture was stirred andrefluxed for 2 hours. The mixture was evaporated till dryness and theproduct was used without further purification, yielding 36.4 g (100%) ofN-[2-(3-methoxybenzoyl)-4-[2-(4-chlorophenyl)1,3-dioxolan-2-yl]phenyl]acetamide(interrn. 5-d).

[0123] e) Potassium tert-butoxide (33 g) was added portionwise at roomtemperature to a solution of interm. (5-d) (36.4 g) in1,2-dimethoxyethane (350 ml) and the mixture was stirred at roomtemperature overnight. The mixture was hydrolized and extracted withDCM. The organic layer was dried, filtered off and evaporated tilldryness. The product was used without further purification, yielding 43g of6-[2-(4-chloro-phenyl)-1,3-dioxolan-2-yl]-4-(3-methoxyphenyl)-2(1H)-quinolinone(interm. 5-e).

[0124] f) A mixture of interrn. (5-e) (43 g) in HCl (3N, 400 ml) andmethanol (150 ml) was stirred and refluxed overnight. The mixture wascooled and filtered off. The precipitate was washed with water anddiethyl ether and dried. The product was used without furtherpurification, yielding 27 g (94%) of6-(4-chlorobenzoyl)-4-(3-methoxyphenyl)-2(1H)-quinolinone (interm. 5-f).

[0125] g) Methyl iodide (1.58 ml) was added to a solution of interm.(5-f) (7.6 g) and benzyl-triethylammonium chloride (BTEAC) (2.23 g) inTHF (80 ml) and sodium hydroxide (40%, 80 ml). The mixture was stirredat room temperature for 2 hours. Water was added and the mixture wasextracted with ethyl acetate. The organic layer was dried, filtered, andthe solvent was evaporated. The residue was purified by flash columnchromatography over silica gel (eluent : DCM 100%). The desiredfractions were collected and the solvent was evaporated, yielding 7.1 g(90%) of6-(4-chlorobenzoyl)-4-(3-methoxyphenyl)-1-methyl-2(1H)-quinolinone(interm. 5-g).

Example A.6

[0126] a)3-(3-Chlorophenyl)-5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-2,1-benzisoxazole(interm. 6-a) was prepared analogous as intermediate (5-b).

[0127] b) A mixture of intermediate (6-a) (30 g) in HCl 3 N (220 ml) andmethanol (165 ml), was stirred at 100° C. for 5 hours. The mixture waspoured into ice and basified with NH₃ (aq.). The precipitate wasfiltered off, washed with water and diethyl ether and dried, yielding24.9 g (93%) of(4-chlorophenyl)[3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl]methanone(interm. 6-b). The product was used without further purification.

[0128] c) Butyllithium in hexanes (10 ml) was added slowly at −70° C.under N₂ flow to a solution of 1-methylimidazole (1.31 g) in THF (30ml). The mixture was stirred at −70° C. for 45 minutes.Chlorotriethylsilane (2.7 ml) was added. The mixture was allowed to warmto 15° C. and cooled to −70° C. Butyllithium (10 ml) was added slowly.The mixture was stirred at −70° C. for 1 hour, allowed to warm to −15°C. and cooled to −70° C. A solution of intermediate (6-b) (4.9 g) in THF(60 ml) was added. The mixture was stirred at −70° C. for 30 minutes,then hydrolyzed with water, extracted with ethyl acetate and decanted.The organic layer was dried, filtered and the solvent was evaporated.The residue (8.2 g) was purified by column chromatography over silicagel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 96/4/0.2) and crystallized from2-propanone/diethyl ether. The precipitate was filtered off and dried,yielding 1.5 g (25%) of(±)-3-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-2,1-benzisoxazole-5-methanol(interm. 6-c).

[0129] d) TiCl₃/15% in H₂O (200 ml) was added at room temperature to asolution of intermediate (6-c) (38 g) in THF (300 ml). The mixture wasstirred at room temperature for 90 minutes. The mixture was poured outon ice, basified with K₂CO₃, filtered over celite, washed with ethylacetate and decanted. The organic layer was dried, filtered and thesolvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1 and95/5/0.1), yielding 18.7 g (49%) of(±)-[2-amino-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)methanone(interm. 6-d).

B. PREPARATION OF THE FINAL COMPOUNDS Example B.1

[0130] 1-Methylimidazole (4.69 ml) in tetrahydrofuran (100 ml) wasstirred at −78° C. A solution of butyllithium in hexanes (2.5 M) (36.7ml) was added dropwise and the mixture was stirred at −78° C. for 15minutes. Chlorothiethylsilane (9.87 ml) was added and the mixture wasbrought to room temperature. The mixture was cooled till −78° C., asolution of butyllithium in hexanes (2.5 M) (36.7 ml) was addeddropwise, the mixture was stirred at −78° C. for 1 hour and brought till−15° C. The mixture was cooled till −78° C., a solution of intermediate(1-d) (20 g) in THF (40 ml) was added and the mixture was brought toroom temperature. The mixture was hydrolized at 0° C. and extracted withethyl acetate. The organic layer was dried, filtered off and evaporatedtill dryness, yielding 36 g of product. The product was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH97/3/0.1). The pure fractions were collected, evaporated, andcrystallized from 2-propanone, CH₃OH and (C₂H₅)₂O. The precipitate wasfiltered off, washed with (C₂H₅)₂O and dried, yielding 12.4 g (52%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone;(comp. 3, mp.233.6° C.).

[0131] In a similar way, but using intermediate (5-g) or intermediate(1-e) instead of intermediate (1-d), respectively(±)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-methoxyphenyl)-1-methyl-2(1H)-quinolinone(comp. 36) and(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-3,4-dihydro-1-methyl-2(1H)-quinolinone(comp. 127) were prepared.

Example B.2

[0132] Hydrochloric acid (60 ml) was added to a solution of intermediate(2) (2.5 g) in THF (10 ml) and the mixture was stirred and heated at100° C. for 3 hours. The mixture was cooled, the precipitate wasfiltered off, washed with water, then with diethyl ether and dried,yielding 2.7 g (100%) of(±)-6-[(1-butyl-1H-imidazol-5-yl)-(4-chloro-phenyl)hydroxymethyl]-4-(3-chlorophenyl)-2(1H)-quinolinone(comp. 8).

Example B.3

[0133] Sodium hydride (0.28 g) was added to a mixture of compound (3) (3g) in DMF (50 ml) under N₂ and the mixture was stirred for 15 minutes.Iodomethane (1.5 ml) was added and the mixture was stirred at roomtemperature for 1 hour. The mixture was hydrolized and extracted withdiethyl ether and methanol. The organic layer was dried, filtered offand evaporated till dryness, yielding 4.4 g of residue. The residue waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 95.5/4.5/0.2). The pure fractions were collected andevaporated. The product was converted into the ethanedioic acid salt(1:1) in 2-propanone and filtered off. The residue was crystallized from2-propanone, diethyl ether and DIPE. The precipitate was filtered off,washed with diethyl ether, dried and recrystallized from 2-propanone,methanol and DIPE. The precipitate was filtered off, washed with diethylether and dried, yielding 0.95 g (25%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)methoxy(1-methly-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinoneethanedioate(1:1).dihydrate; (comp. 4, mp. 154.6° C.).

Example B.4

[0134] Iodomethane (0.38 ml) was added dropwise at room temperature to asolution of compound (8) (2.44 g) and N,N,N-triethylbenzenemethanaminiumchloride (0.54 g) in tetrahydrofuran (30 ml) and sodium hydroxide (40%)(30 ml) and the mixture was stirred at room temperature for 3 hours.Water was added and the mixture was extracted with ethyl acetate. Theorganic layer was dried, filtered off and evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 96.5/3.5/0.1). The pure fractions were collected, evaporated andcrystallized from 2-propanone and DIPE. The precipitate was filteredoff, washed with diethyl ether and dried, yielding 1.4 g (56%) of(±)-4-(3-chlorophenyl)-6-[(1-butyl-1H-imidazol-5-yl)(4-chlorophenyl)hydroxymethyl]-1-methyl-2(1H)-quinolinone; (comp. 9, mp. 174.6° C.).

Example B.5

[0135] Iodomethane (1.4 ml) was added to a mixture of(±)-6-[(4-chlorophenyl)-1H-imidazol-4-ylmethyl]-1-methyl-4-phenyl-2(1H)-quinolinone(7.5 g) and benzyltriethylammonium chloride (2 g) in THF (75 ml) andsodium hydroxide (75 ml) and the mixture was stirred at room temperaturefor 1 hour. Water was added and the mixture was extracted with ethylacetate. The organic layer was dried, filtered off and evaporated tilldryness. The residue was purified by column chromatography over silicagel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98.5/1.5/0.1). The pure fractions werecollected and evaporated. Fraction 1 (3.5 g) was recrystallized fromdiethyl ether, yielding 3.3 g (42%) of(±)-6-[(4-chlorophenyl)(1-methyl-1H-imidazol-4-yl)methyl]-1-methyl-4-phenyl-2(1H)-quinolinone;mp. 149.9° C (comp. 44). Fraction 2 was recrystallized from 2-propanone,methanol and diethyl ether, yielding 1.6 g (20%) of(±)-6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-phenyl-2(1H)-quinolinone(comp. 2, mp. 96.8° C.).

Example B.6

[0136] Sodium borohydride (5.6 g) was added portionwise at 0° C. underN₂ to compound (3) (7.2 g) dissolved in trifluoroacetic acid (150 ml)and the mixture was stirred at room temperature overnight. The mixturewas poured into ice, basified with NaOH 3N, then concentrated NaOH andextracted with ethyl acetate. The organic layer was dried, filtered offand evaporated till dryness. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 95/5). The purefractions were collected and evaporated, yielding 4.3 g (62%) offraction 1; 0.2 g (3%) of fraction 2 and 2 g (29%) of fraction 3.Fraction 1 was converted into the ethanedioic acid salt (1:1) in2-propanone and diethyl ether. The precipitate was filtered off, washedwith diethyl ether and dried, yielding 4.7 g (55%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinoneethanedioate(1:1).mono-hydrate (comp. 5, mp. 157.4° C.).

Example B.7

[0137] A solution of compound 90 (4.2 g) in 1,2-dimethoxyethane (70 ml)was stirred under N₂ for 30 minutes. Iodomethane (0.83 ml), followed bypotassium tert-butoxide (2 g) were added portionwise and the mixture wasstirred at room temperature for 30 minutes. Water was added and themixture was extracted with ethyl acetate. The organic layer was dried,filtered off and evaporated. The residue was purified by columnchromatography over silica gel (eluent:cyclohexane/2-propanol/NH₄OH85/5/0.5 to 80/20/1) and converted into the ethanedioic acid salt,crystallized from 2-propanone and filtered off, yielding 1.16 g (23.6%)of(±)-4-(3-chlorophenyl)-6-[1-(4-chloro-phenyl)-1-(1-methyl-1H-imidazol-5-yl)ethyl]-1-methyl-2(1H)-quinolinone.ethanedioate(1:1); (comp. 12, mp. 203.9° C.).

[0138] In a similar way, but replacing iodomethane by dichloromethane ordibromomethane, respectively(±)-6-[2-chloro-1-(4-chlorophenyl)-1-(1-methyl-1H-imidazol-5-yl)ethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinoneethanedioate (1:1) (comp. 69) and(±)-6-[2-bromo-1-(4-chlorophenyl)-1-(1-methyl-1H-imidazol-5-yl)ethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone(comp. 70) were prepared.

Example B.8

[0139] a) Compound (3) (3 g) was separated (into its enantiomers) andpurified by high-performance liquid chromatography over Chiracel OD (20μm; eluent:hexane/ethanol 50/50). The pure (A)-fractions were collected,and the solvent was evaporated, yielding 1.6 g ((A); LCI:>99%). The pure(B)-fractions were collected, and the solvent was evaporated, yielding1.5 g ((B); LCI:>99%). The (A)-residue was dissolved in 2-propanol andconverted into the ethanedioic acid salt (1:1). The precipitate wasfiltered off and dried, yielding 0.6 g (17%) of(+)-4-(3-chlorophenyl)-6-[(4-chloro-phenyl)-hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-20quinolinoneethanedioate (1:1) ; [α]_(D) ²⁰=+17.96° (c=1% in methanol) (comp. 23).The (B)-residue was dissolved in 2-propanol and converted into theethanedioic acid salt (1:1). The precipitate was filtered off and dried,yielding 0.6 g (17%)(−)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinoneethanedioate(1:1); [α]_(D) ²⁰=−18.87° (c=1% (w/v) in methanol) (comp.24).

[0140] b) Compound 14 (4 g) was separated (into its enantiomers) andpurified by chiral column chromatography over Chiralcel OD (25 cm;eluent: 100% ethanol; flow: 0.5 ml/min; wavelength: 220 nm). The pure(A)-fractions were collected, and the solvent was evaporated. Thisresidue was dissolved in DCM (100 ml), filtered, and the filtrate wasevaporated. The residue was stirred in DIPE (100 ml), filtered off anddried, yielding 1.3 g (−)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chloro-phenyl)-1-methyl-2(1H)-quinolinone([α]_(D) ²⁰=−6.16° (c=0.67% (w/v) in methanol)(comp. 74).

[0141] The pure (B)-fractions were collected and evaporated. The residuewas crystallized from 2-propanol. The precipitate was filtered off,yielding 1.3 g(+)-6-[amino(4-chloro-phenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone([α]_(D) ²⁰=+22.860° (c=0.98% (w/v) in methanol) (comp. 75).

Example B.9

[0142] Air was bubbled through a solution of compound (47) (3.6 g) inTHF (40 ml) for 30 minutes. 2-Methyl-2-propanol potassium salt (4.4 g)was added. The mixture was stirred at room temperature for 3 hours,hydrolyzed and then extracted with DCM. The organic layer was separated,dried, filtered and the solvent was evaparated, yielding 2.9 g ofproduct. The product was purified by column chromatography over silicagel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97.5/2.5/0.1). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom 2-propanone/DIPE. The precipitate was filtered off and dried,yielding 1.3 g (35%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-4-yl)methyl]-1-methyl-2(1H)-quinolinone(comp. 48).

Example B.10

[0143] A mixture of (+)-4-[(4-chlorophenyl)(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)hydroxymethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide(2.4 g) in hydrochloric acid (10 ml), water (30 ml) and methanol (15 ml)was stirred and heated at 110° C. for 14 hours. The mixture was cooled,basified with NH₃ (aq.) and extracted with DCM. The organic layer wasdried, filtered off and evaporated till dryness. The residue waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.2). The pure fractions were collected andevaporated. The residue (1.25 g) was crystallized from 2-propanone/DIPE,yielding 1 g (48.3%) of(±)-6-[(4-chlorophenyl)hydroxy(1H-imidazol-4-yl)methyl]-1-methyl-4-phenyl-2(1H)-quinolinonemonohydrate (comp. 43).

Example B.11

[0144] Compound (3) (4 g) was dissolved in DCM (10 ml) and acetic acid(5.6 ml) at 45° C. Zinc chloride (5.5 g), followed by cyanoacetic acid(3.5 g) were added. The mixture was stirred at 120° C. for 3 hours andthen at 160° C. for 10 hours. Water was added and the mixture wasextracted with DCM. The organic layer was washed with K₂CO₃10%, dried,filtered, and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH96/4/0.2), crystallized from 2-propanone/DIPE, filtered off and dried,yielding 1.95 g (45%) of(±)-4-(3-chlorophenyl)-β-(4-chlorophenyl)-1,2-dihydro-1-methyl-β-(1-methyl-1H-imidazol-5-yl)-2-oxo-6-quinolinepropanenitrile; (comp. 25,mp. 151.3° C.).

Example B.12

[0145] Sulfuric acid (1 ml) was added dropwise to acetonitrile (30 ml),while stirring. Compound 3 (3 g) was added. The mixture was stirred at80° C. for 3 hours and then cooled. K₂CO₃ 10% was added and the mixturewas extracted with ethyl acetate. The organic layer was separated,dried, filtered and the solvent was evaporated till dryness. The residue(3.58 g) was dissolved in 2-propanone and converted into the ethanedioicacid salt (1:1)., The precipitate was filtered off, dried andcrystallized from 2-propanone/CH₃OH. The precipitate was filtered offand dried, yielding 3.5 g (92%) of(±)-N-[(4-chlorophenyl)[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl](1-methyl-1H-imidazol-5-yl)methyl]acetamideethanedioate (1:1) (comp. 56).

Example B.13

[0146] NH₃ (aq.) (40 ml) was added at room temperature to a mixture ofintermediate 4 (7 g) in THF (40 ml). The mixture was stirred at 80° C.for 1 hour, then hydrolyzed and extracted with DCM. The organic layerwas separated, dried, filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:toluene/2-propanol/NH₄OH 80/20/1). The pure fractions were collected andthe solvent was evaporated, yielding 4.4g(±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone(comp. 14).

Example B.14

[0147] A solution of compound 36 (6.2 g) in DCM (140 ml) was cooled andtribromoborane (32 ml) was added dropwise. The mixture was stirred atroom temperature for tho days.

[0148] The mixture was poured out into ice water, basified with NH₃(aq.) and extracted with CH₂Cl₂/CH₃OH. The organic layer was separated,dried, filtered and the solvent was evaporated till dryness, yielding 6g (100%) of(±−)-6-[(4-chlorophenyl)-hydroxy-(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-hydroxyphenyl)-1-methyl-2(1H)-quinolinone(comp. 54).

Example B.15

[0149] A mixture of compound 54 (2.5 g),2-chloro-N,N-dimethyl-ethanamine (1.9 g) and potassium carbonate (2.2 g)in ACN (50 ml) and DMF (50 ml) was stirred at 100° C. overnight. Thesolvent was evaporated till dryness. The residue was taken up inCH₂Cl₂/water and decanted. The organic layer was dried, filtered and thesolvent was evaporated. The residue (2.7 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1 to90/10/0.1). The pure fractions were collected and the solvent wasevaporated. The residue was converted into the ethanedioic acid salt(1:1) in 2-propanone. The precipitate was filtered off, washed with2-propanone/diethyl ether and dried. The residue was converted into thefree base. The precipitate was filtered off and dried. The residue wascrystallized from diethyl ether. The precipitate was filtered off anddried, yielding 0.35 g (12%) of(±)-6-[(4-chloro-phenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-[3-[2-(dimethylamino)ethoxy]-phenyl]-1-methyl-2(1H)-quinolinone(comp. 62).

Example B.16

[0150] P₄S₁₀ (12 g) was added to a mixture of compound 90 (6 g) inpyridine (72 ml). The mixture was stirred and refluxed for 6 hours. Icewater was added. The precipitate was filtered off, washed with water andtaken up in DCM. The organic layer was separated, dried, filtered andthe solvent was evaporated till dryness. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH97.5/2.5/0.1). The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from 2-propanone/diethyl ether.The precipitate was filtered off and dried, yielding 1 g of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinethione(comp. 128).

Example B.17

[0151] A mixture of ethyl malonyl chloride (6.4 ml) in DCM (50 ml) wasadded dropwise at room temperature to a solution of intermediate (6-d)(15 g) and pyridine (10.7 ml) in DCM (150 ml). The mixture was stirredat room temperature overnight. Water was added and the mixture wasdecanted. The organic layer was dried, filtered and the solvent wasevaporated. The residue (21 g) was purified by column chromatographyover silica gel (eluent: CH₂Cl₂/2-propanol/NH₄OH 92/8/0.4). The desiredfractions were collected and the solvent was evaporated, yielding 10.9 g(60%) of (±)-ethyl 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,2-dihydro-2-oxo-3-quinolinecarboxylate(comp. 144).

Example B.18

[0152] a) A mixture of benzoyl chloride (3.1 ml) in DCM (25 ml) wasadded dropwise at room temperature to a solution of interm. (6-d) (7 g)and pyridine (5 ml) in DCM (70 ml). The mixture was stirred at roomtemperature for 45 minutes. Water was added and the mixture wasdecanted. The organic layer was dried, filtered and the solvent wasevaporated, yielding 8.8 g of(±)-N-[2-(3-chlorobenzoyl)-4-[(4-chlorophenyl)-hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl]benzeneacetamide(interm. 7). The product was used without further purification.

[0153] b) Potassium tert-butoxide (8.7 g) was added to a mixture ofintermediate 7 (8.8 g) in DME (70 ml). The mixture was stirred at 50° C.for 3 hours. Water (5 ml) was added and the solvent was evaporated,yielding 8.5 g of(±)-4-(3-chlorophenyl)-6-[(4-chloro-phenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-3-phenyl-2(1H)-quinolinone (comp. 140).

Example B.19

[0154] NH₃ (aq.) (150 ml) was cooled to 5° C. A solution of(±)-4-(3-chlorophenyl)-1-methyl-6-[1-(4-methylphenyl)-1-(4-methyl-4H-pyrrol-3-yl)ethyl]-2(1H)-quinolinonehydrochloride (16.68 g) in THF (150 ml) was added. The mixture wasstirred at room temperature for 2 hours, decanted and extracted withethyl acetate. The organic layer was dried, filtered and the solvent wasevaporated till dryness. The reaction was carried out twice. Theresidues were combined and purified by column chromatography over silicagel (eluent: toluene/2-propanol/NH₄OH 70-29-1). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom CH₂Cl₂/CH₃OH/CH₃CN. The precipitate was filtered off and the motherlayer was evaporated till dryness, purified by column chromatography(eluent: CH₃OH/NH₄OAc (0.5% in H₂O) 70/30). Two pure fractions werecollected and their solvents were evaporated till dryness. Fraction 2was recrystallized from CH₂Cl₂/diethyl ether. The precipitate wasfiltered off and dried, yielding 0.8 g of(±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-3-chloro-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone(comp. 143).

Example B.20

[0155] Sulfuric acid (1 ml) was added at room temperature to a solutionof compound 3 (3.5 g) in methoxyacetonitrile (10 ml) and the mixture wasstirred and heated at 80° C. for 3 hours. The mixture was couled, pouredinto ice, basified with NH₃ (aq.) and filtered, off. The precipitate wastaken up in DCM. The organic layer was separated, dried, filtered andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 96/4/0.3).The pure fractions were collected and the solvent was evaporated. Theresidue was converted into the hydrochloric acid salt (1:1) andcrystallized from ACN. The precipitate was filtered off and dried,yielding 2.5 g (58%) of(±)-N-[(4-chlorophenyl)[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl](1-methyl-1H-imidazol-5-yl)methyl]-2-methoxyacetamidemonohydrochloride (comp. 89).

Example B.21

[0156] A solution of intermediate (4) (3.3 g) in THF (10 ml) was addeddropwise at room temperature to a solution of methanamine in water (40ml). The mixture was stirred at 80° C. for 45 minutes, taken up in waterand extracted with DCM. The organic layer was separated, dried, filteredand the solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.3 and95/5/0.3). The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from diethyl ether. Theprecipitate was filtered off and dried, yielding 0.89 g (28%) of(±)-4-(3-chlorophenyl)-6-[(4-chloro-phenyl)(methylamino)-(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinonemonohydrate (comp. 61).

[0157] Tables 1 to 8 list the compounds that were prepared according toone of the above Example s and table 9 lists both the experimental(column heading “exp.”) and theoretical (column heading “theor.”)elemental analysis values for carbon, hydrogen and nitrogen of thecompounds as prepared in the experimental part hereinabove. TABLE 1

Co. Ex. No. No. R¹ R^(4a) R⁸ Physical data 3 B.1 CH₃ CH₃ OH mp. 233.6°C. 4 B.3 CH₃ CH₃ OCH₃ mp. 140-160° C.; .C₂H₄O₄.H₂O 5 B.6 CH₃ CH₃ H mp.165° C.; .C₂H₄O₄.H₂O 6 B.5 CH₃ CH₂CH₃ H mp. 180° C.; .C₂H₄O₄.1/2H₂O 7B.2 H CH₃ H mp. 260° C. 8 B.2 H (CH₂)₃CH₃ OH — 9 B.4 CH₃ (CH₂)₃CH₃ OHmp. 174° C. 10 B.3 H CH₃ OCH₂COOCH₂CH₃ mp. 185° C.; .3/2C₂H₂O₄ 11 B.3CH₃ CH₃ O(CH₂)₂N(CH₃)₂ mp. 120° C. 12 B.7 CH₃ CH₃ CH₃ mp. 210° C.;.C₂H₄O₄ 13 B.7 CH₃ CH₃ CH₂CH₃ mp. 196° C. .C₂H₂O₄ 14 B.13 CH₃ CH₃ NH₂mp. 220° C. 72 B.13 CH₃ CH₃ NH₂ .3/2-(E)-C₄H₄O₄ 73 B.13 CH₃ CH₃ NH₂.2HCl 74 B.8b CH₃ CH₃ NH₂ (−)- 75 B.8b CH₃ CH₃ NH₂ (+)-; mp. 232.4° C.15 B.3 CH₃ CH₃ O(CH₂)₃OH mp. 135° C. 16 B.3 CH₃ CH₃ O(CH₂)₂CH₃ mp. 180°C.; .C₂H₂O₄.3/2(H₂O) 17 B.3 CH₃ CH₃ O(CH₂)₂O—C₆H₅ mp. 144° C.;.3/2(C₂H₂O₄) 18 B.2 H CH(CH₃)₂ OH — 19 B.4 CH₃ CH(CH₃)₂ OH mp. 254° C.20 B.2 H (CH₂)₂OCH₃ OH mp. 112° C. 21 B.4 CH₃ (CH₂)₂OCH₃ OH mp. 192° C.22 B.3 CH₃ CH₃ O(CH₂)₂OH mp. 198° C. 23 B.8a CH₃ CH₃ OH mp. 150-200° C.;(°)-; .C₂H₂O₄ 24 B.8a CH₃ CH₃ OH mp. 150-200° C.; (−)-; .C₂H₂O₄ 25 B.11CH₃ CH₃ CH₂—CN mp. 154° C. 27 B.2 H (CH₂)₃OCH₃ OH — 28 B.4 CH₃(CH₂)₃OCH₃ OH mp. 196° C.; .H₂O 29 B.3 CH₃ CH₃ O(CH₂)₃OCH₂CH₃ mp. 105°C.; .3/2(H₂O) 31 B.2 H CH₃ OH >260° C. 32 B.6 CH₃ (CH₂)₂OCH₃ H mp. 140°C.; .3/2(C₂H₂O₄) 33 B.6 CH₃ (CH₂)₃OCH₃ H mp. 180° C.; .HCl 56 B.12 CH₃CH₃ —NHCOCH₃ .C₂H₂O₄ 58 B.11 CH₃ CH₃ —CH₂COOCH₂CH₃ .C₂H₂O₄.3/2(H₂O) 60B.11 CH₃ CH₃ 1-imidazolyl — 61 B.21 CH₃ CH₃ —NH—CH₃ mp. 164° C. 65 B.2 H(CH₂)₃SOCH₃ OH .H₂O 66 B.13 CH₃ CH₃ —N(CH₃)₂ .2C₂H₂O₄.H₂O mp. 160° C. 67B.13 CH₃ CH₃ —NH—(CH₂)₂OCH₃ mp. 216° C. 68 B.13 CH₃ CH₃ —NH—(CH₂)₂—OH —69 B.7 CH₃ CH₃ —CH₂Cl .2C₂H₂O₄ mp. 220° C. 70 B.7 CH₃ CH₃ —CH₂Br — 71 *CH₃ CH₃ —CH₂OH .2C₂H₂O₄ 76 B.4 —(CH₂)₂OCH₃ CH₃ OH mp. 150° C. 77 * CH₃CH₃ —CH₂OCH₃ .2C₂H₂O₄ mp. 166° C. 78 B.13 CH₃ CH₃ —NH—OCH₃ mp. 170° C.79 B.20 CH₃ CH₃ —NH—CONH₂ .2H₂O 80 ** CH₃ CH₃ —CH₂CONH₂ — 81 B.13 CH₃CH₃ —NH—OH — 82 B.13 CH₃ CH₃ —NH(CH₂)₂N(CH₃)₂ — 83 B.4 (CH₂)₂N(CH₃)₂ CH₃OH .3/2C₂H₂O₄ .3/2H₂O mp. 200° C. 84 * CH₃ CH₃ —CH₂N(CH₃)₂ .C₂H₂O₄ mp.210° C. 85 B.4 CH₃ CH₃ —N(CH₃)₂ — 86 B.4 CH₃ CH₃ NHCOCH₂N(CH₃)₂ — 87 B.4CH₃ CH₃ —NH(CH₂)₉CH₃ — 88 B.4 CH₃ CH₃ —NH(CH₂)₂NH₂ — 89 B.20 CH₃ CH₃—NHCOCH₂OCH₃ .HCl mp. 220° C. 90 B.6 CH_(3 CH) ₃ H — 91 B.20 CH₃ CH₃—NHCOCH₂C₆H₅ .C₂H₂O₄.H₂O mp. 170° C. 92 B.20 CH₃ CH₃ —NHCOC₆H₅ mp. 242°C. 93 B.20 CH₃ CH₃ —NHCOCONH₂ .C₂H₂O₄.H₂O mp. 186° C. 94 B.13 CH₃ CH₃—NHC₆H₅ mp. 165° C.

[0158] TABLE 2

Co. Ex. No. No. R¹ R² R^(4a) R⁵ R⁸ Physical data 1 B.1 CH₃ H CH₃ H OHmp. >250° C. 2 B.5 CH₃ H CH₃ H H mp. 100-110° C. 26 B.1 CH₃ 3-Cl CH₃2-CH₃ OH mp. 200° C. 30 B.6 CH₃ 3-Cl CH₃ 2-CH₃ H mp. 120-140° C.;.3/2(C₂H₂O₄).H₂O 34 B.1 CH₃ 3-O—CH₂—CH₃ CH₃ H OH mp. 190° C. 35 B.6 CH₃3-O—CH₂—CH₃ CH₃ H H mp. 160-180° C.; .HCl.H₂O 36 B.1 CH₃ 3-O—CH₃ CH₃ HOH mp. 210° C. 37 B.1 CH₃ 3-O—(CH₂)₂—CH₃ CH₃ H OH mp. 150-160° C. 38 B.1CH₃ 3-O—(CH₂)₃—CH₃ CH₃ H OH mp. 150-160° C. 49 B.1 CH₃ 4-O—CH₂—CH₃ CH₃ HOH mp. 184.2° C. 50 B.1 CH₃ 3-O—CH—(CH₃)₂ CH₃ H OH mp. 147.1° C. 51 B.6CH₃ 3-O—(CH₂)₃—CH₃ CH₃ H H mp. 164.2° C.; .3/2(C₂H₂O₄) 52 B.6 CH₃3-O—(CH₂)₂—CH₃ CH₃ H H .3/2(C₂H₂O₄) 53 B.6 CH₃ 3-O—CH—(CH₃)₂ CH₃ H H mp.133.9° C.; .C₂H₂O₄.H₂O 54 B.14 CH₃ 3-OH CH₃ H OH — 64 B.10 CH₃ 3-OH CH₃H OH .HCl.H₂O 55 B.6 CH₃ 3-OH CH₃ H H mp. >250° C. 57 B.1 CH₃ 2-OCH₂CH₃CH₃ H OH — 59 B.13 CH₃ 3-OCH₂CH₃ CH₃ H NH₂ — 95 B.8a CH₃ 3-OCH₂CH₃ CH₃ HNH₂ (A) 96 B.8a CH₃ 3-OCH₂HC₃ CH₃ H NH₂ (B) 62 B.15 CH₃ 3-O(CH₂)₂N(CH₃)₂CH₃ H OH — 63 B.11 CH₃ 3-O(CH₂)₂—OH CH₃ H OH — 97 B.1 CH₃ 3-CH₂CH₃ CH₃ HOH — 98 B.13 CH₃ 3-CH₂CH₃ CH₃ H NH₂ mp. 240° C. 99 B.1 CH₃ 3-(CH₂)₂CH₃CH₃ H OH — 100 B.13 CH₃ 3-(CH₂)₂CH₃ CH₃ H NH₂ — 101 * CH₃ 3-O—(CH₂)₂OCH₃CH₃ H OH .3/2(C²⁻H₂O₄) mp. 193° C. 102 B.1 CH₃ 3-CH₃ CH₃ H OH mp. >250°C. 103 B.13 CH₃ 3-CH₃ CH₃ H NH₂ — 104 B.1 CH₃ 3-Br CH₃ H OH — 105 B.13CH₃ 3-Br CH₃ H NH₂ — 106 B.1 CH₃ 3-O—CF₃ CH₃ H OH — 107 B.13 CH₃ 3-O—CF₃CH₃ H NH₂ mp. 168° C. 108 B.1 CH₃ 3-C₆F₅ CH₃ H OH — 109 B.13 CH₃ 3-C₆F₅CH₃ H NH₂ — 110 B.1 CH₃ 3-F CH₃ H OH — 111 B.13 CH₃ 3-F CH₃ H NH₂np. >250° C. 112 B.12 CH₃ 3-(E)- CH₃ H OH mp. >250° C. CH═CH—CH₃ 113 B.2H 3-Cl CH₃ 3-Cl OH — 114 B.4 CH₃ 3-Cl CH₃ 3-Cl OH — 115 B.1 CH₃ 3-Cl H3-CH₃ OH — 116 B.4 CH₃ 3-Cl CH₃ 3-CH₃ OH — 117 ** CH₃ 3-CN CH₃ H OH —160 B.1 CH₃ 3-CF₃ CH₃ H OH —

[0159] TABLE 3

Co. No. No. No. R¹ R⁸ Physical data 39 B.1CH₂CONHCH(COOCH₃)(CH₂CH(CH₃)₂) H mp. 240° C. (S) 40 B.4 CH₂-2-quinolinylH mp. 240° C.; .2 HCl 41 B.4 CH₂CONHCH(COOCH₃)(CH₂CH(CH₃)₂) OH mp. >260°C. (S)

[0160] TABLE 4

Co. Ex. No. No. R² R⁴ R^(5a) R⁶ R⁸ Physical data 42 B.6 H H H 4-Cl H mp.170° C.; .C₂H₂O₄.1/2 H₂O 43 B.10 H H H 4-Cl OH mp. 180° C.; .H₂O 44 B.5H H CH₃ 4-Cl H mp. 152° C. 45 B.6 3-Cl H H 4-Cl H mp. 175° C.; .C₂H₂O₄46 B.5 3-Cl H CH₂CH₃ 4-Cl H mp. 132° C.; .C₂H₂O₄ 47 B.5 3-Cl H CH₃ 4-ClH mp. 115° C.; .3/2 C₂H₂O₄ 48 B.9 3-Cl H CH₃ 4-Cl OH mp. 230° C. 118 B.43-Cl 3-CH₃ CH₃ 4-Cl OH mp. 222° C.

[0161] TABLE 5

Co. No. Ex. No. —R²—R³— R⁶ R⁸ 119 B.1 —O—CH₂—O— 4-Cl OH 120 B.13—O—CH₂—O— 4-Cl NH₂ 121 B.1 —O—CH₂—CH₂—O— 4-Cl OH 122 B.13 —O—CH₂—CH₂—O—4-Cl NH₂ 123 B.1 —O—CH═CH— 4-Cl OH

[0162] TABLE 6

Co. Ex. Physical No. No. X

R² R³ R¹⁶ R⁸ data 124 B.1 O doub- 3-OCH₃ 4-OCH₃ 5-OCH₃ OH mp. le 230° C.125 B.13 O doub- 3-OCH₃ 4-OCH₃ 5-OCH₃ NH₂ mp. le 218° C. .C₂H₂O₄ 126 B.1O sing- 3-Cl H H OH mp. le 160° C. 127 B.1 O single 3-Cl H H OH — 128B.16 S doub- 3-Cl H H H — le

[0163] TABLE 7

Co. Ex. No. No. R¹ R¹⁷ R¹⁸ R¹⁹ R⁸ Physical data 129 B.17 H CN H H H —130 B.4 CH₃ CN H H H mp. 202° C. 131 B.17 H CN H H OH — 132 B.4 CH₃ CN HH OH — 133 B.17 H CN H H —CH₂CN — 134 B.4 CH₃ CN H H —CH₂CN mp. 138° C.135 B.18 H CH₃ H H OH — 136 B.4 CH₃ CH₃ H H OH — 137 B.13 CH₃ CH₃ H HNH₂ mp. >250° C. 138 B.18 H C₆H₅ H H H ‘3 139 B.4 CH₃ C₆H₅ H H H.3/2(C₂H₂O₄) mp. 180° C. 140 B.18 H C₆H₅ H H OH — 141 B.4 CH₃ C₆H₅ H HOH — 142 B.13 CH₃ C₆H₅ H H NH₂ — 143 B.13 CH₃ Cl H H NH₂ — 144 B.17 H—COOCH₂CH₃ H H OH — 145 B.4 CH₃ —COOCH₂CH₃ H H OH ‘3 146 B.1 CH₃ H 8-CH₃H OH — 147 B.13 CH₃ H 8-CH₃ H NH₂ .H₂O 148 B.1 CH₃ H 7-Cl H OH — 149 B.1CH₃ H 7-CH₃ H OH — 150 B.1 CH₃ H 5-CH₃ H OH — 151 B.1 CH₃ H 8-OCH₃ H OH— 161 B.1 CH₃ H 7-CH₃ 8-CH₃ OH mp. 255° C.

[0164] TABLE 8

Co. Ex. No. No. R² R³ R⁶ R⁷ R⁸ Physical data 152 B.1 3-OCH₂CH₃ H4-OCH₂CH₃ H OH .3/2(C₂H₂O₄) 153 B.1 3-Cl H H H OH ‘3 154 B.1 3-Cl H4-CH₃ H OH — 155 B.1 3-Cl H 4-OCH₃ H OH — 156 B.1 3-Cl H 4-CF₃ H OH —157 B.1 3-Cl H 2-Cl 4-Cl OH — 158 B.1 3-Cl 5-Cl 4-Cl H OH — 159 B.1

H 4-Cl H OH — 162 B.1 3-Cl H 4-S—CH₃ H OH mp. 169° C. .C₂H₂O₄.H₂O; 163B.1 3-Cl H 4-N(CH₃)₂ H OH mp. decomposes >172° C. 164 B.1 3-Cl H—CH═CH—CH═CH—* OH .C₂H₂O₄

[0165] TABLE 9 Comp. Carbon Hydroen Nitrogen No. Exp. Theor. Exp. Theor.Exp. Theor. 57 67.78 69.66 4.82 5.24 7.83 8.40 58 58.59 58.50 4.58 4.765.96 6.20 59 69.68 69.80 5.38 5.45 11.06 11.23 60 65.89 66.67 4.35 4.2911.30 12.96 62 66.51 68.56 5.74 5.75 9.67 10.32 63 66.64 67.50 5.29 5.087.63 8.14 64 62.20 61.60 4.70 4.79 7.97 7.98 65 58.90 59.59 4.42 4.666.79 7.19 68 64.29 65.29 4.87 4.91 10.13 10.50 71 60.68 60.62 3.86 4.246.87 7.07 73 54.33 57.67 4.51 4.30 9.26 9.96 74 66.64 66.26 4.28 4.5311.33 11.45 75 66.26 66.26 4.39 4.53 11.30 11.45 79 59.89 59.16 4.654.79 12.18 12.32 80 64.27 65.54 4.71 4.55 10.36 10.54 81 64.27 64.174.44 4.39 10.92 11.09 82 65.98 66.43 5.88 5.57 11.61 12.49 85 66.2067.31 5.22 5.06 10.44 10.83 86 64.83 64.81 4.96 5.09 12.12 12.19 8769.63 70.58 6.88 6.72 8.70 8.90 88 65.21 65.42 5.10 5.11 13.22 13.15 9771.38 71.97 5.60 5.41 8.17 8.68 98 71.38 72.11 5.58 5.63 11.31 11.60 10071.92 72.50 5.65 5.88 10.92 11.27 103 70.72 71.71 5.42 5.37 11.80 11.95104 60.56 60.63 3.99 3.96 7.84 7.86 105 60.33 60.75 3.72 4.15 10.2810.49 106 62.37 62.29 3.71 3.92 7.71 7.78 108 74.22 74.50 4.94 4.93 7.837.90 109 74.17 74.64 5.23 5.12 10.60 10.55 110 68.17 68.43 4.28 4.478.75 8.87 115 65.98 66.13 4.08 4.32 8.53 8.57 116 66.49 66.67 4.38 4.608.47 8.33 117 67.97 69.93 4.60 4.40 11.14 11.65 120 67.35 67.40 4.624.65 11.14 11.23 121 67.32 67.77 4.72 4.71 7.78 8.18 122 67.88 67.904.72 4.91 10.88 10.92 123 69.75 70.23 4.77 4.47 8.06 8.47 128 65.8866.12 4.24 4.32 8.37 8.57 132 65.20 65.25 3.77 3.91 10.42 10.87 13666.77 66.67 4.64 4.60 8.34 8.33 142 69.26 70.09 4.42 4.63 9.59 9.91 14564.36 64.06 4.19 4.48 7.49 7.47 148 61.88 61.79 3.65 3.84 7.88 8.01 15066.56 66.67 4.64 4.60 8.08 8.33 151 64.76 64.62 4.86 4.45 7.80 8.07 15370.99 71.13 5.17 4.86 9.25 9.22 154 71.67 71.56 5.08 5.15 9.14 8.94 15861.72 61.79 3.76 3.84 7.96 8.01 159 69.28 69.50 5.21 5.29 10.01 10.13160 62.71 64.19 3.91 4.04 7.36 8.02

C. PHARMACOLOGICAL EXAMPLE

[0166] C.1 Inhibition of Smooth Muscle Cell Proliferation.

[0167] The effects of the compounds of the present invention werestudied in human pulmonary artery smooth muscle cells (PASMC), humancoronary artery smooth muscle cells (CASMC), and rat A10 arterial smoothmuscle cells growing under standard tissue culture conditions. CASMC andPASMC cell cultures were purchased from Clonetics (San Diego, Calif.).A10 smooth muscle cells were purchased from the American Type CultureCollection (Bethesda, Md.). Cells were inoculated at an initial celldensity of 50,000 cells per well in six-well plastic cluster tissueculture dishes in 3.0 ml of complete growth medium. Test compounds weredissolved in dimethysulfoxide (DMSO) and added in a 3 μl volume to eachwell to produce the desired concentrations of said test compound (5, 10,50, 100 and 500 nM final concentrations). Cells were incubated for sixdays. On day 4, fresh medium plus a fresh solution containing the testcompound were added to the cell cultures. On day 6, the growth mediumwas removed by aspiration. The cells were detached by trypsinizing in1.0 ml of trypsin-EDTA solution. The cell suspensions were transferredto 20 ml of an isotonic diluent and 0.5 ml of the diluted cellsuspension was counted with a Coulter particle counter. Cell counts fromtest compound-treated cultures were normalized to cell counts obtainedfrom DMSO-treated controls and expressed as percent inhibition. IC₅₀values (concentration of test compound producing a 50% inhibition ofcell proliferation) were derived from the inhibition data. These resultsare summarized in Table C.1. TABLE C.1 Inhibition of Smooth Muscle CellProliferation IC₅₀ (nM) Cell Line Co. No. 75 A10 14 PASMC 24 CASMC 16

1. A method of treating vascular proliferative disorders in awarm-blooded animal which comprises administering to said warm-bloodedanimal a prophylactically or therapeutically effective amount of acompound of formula (I),

a stereoisomeric form thereof, a pharmaceutically acceptable acid orbase addition salt thereof, wherein the dotted line represents anoptional bond; X is oxygen or sulfur; R¹ is hydrogen, C₁₋₁₂alkyl, Ar¹,Ar²C₁₋₆alkyl, quinolinylC₁₋₆alkyl, pyridylC₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, mono- or di(C₁-₆alkyl)aminoC₁₋₆alkyl,aminoC₁₋₆alkyl, or a radical of formula -Alk¹-C(═O)—R⁹, -Alk¹-S(O)—R⁹ or-Alk¹-S(O)₂—R⁹, wherein Alk¹is C₁₋₆alkanediyl, R⁹ is hydroxy, C₁₋₆alkyl,C₁₋₆alkyloxy, amino, C₁₋₈alkylamino or C₁₋₈alkylamino substituted withC₁₋₆alkyloxycarbonyl; R², R³ and R¹⁶ each independently are hydrogen,hydroxy, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkyloxy, aminoC₁₋₆alkyloxy, mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹, Ar²C₁₋₆alkyl, Ar²oxy,Ar²C₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, trihalomethyl,trihalomethoxy, C₂-₆alkenyl, 4,4-dimethyloxazolyl; or when on adjacentpositions R² and R³ taken together may form a bivalent radical offormula —O—CH₂—O—  (a-1),—O—CH₂—CH₂—O—  (a-2),—O—CH═CH—  (a-3),—O—CH₂—CH₂—  (a-4),—O—CH₂—CH₂—CH₂—  (a-5),or—CH═CH—CH═CH—  (a-6); R⁴ and R⁵ each independently are hydrogen, halo,Ar¹, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl , C₁₋₆alkyloxy,C₁₋₆alkylthio, amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylS(O)C₁₋₆alkyl or C₁₋₆alkylS(O)₂C₁-₆alkyl; R⁶ and R⁷ eachindependently are hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxy,Ar²oxy, trihalomethyl, C₁₋₆alkylthio, di(C₁₋₆alkyl)amino, or when onadjacent positions R⁶ and R⁷ taken together may form a bivalent radicalof formula —O—CH₂—O—  (c-1), or—CH═CH—CH═CH—  (c-2); R⁸ is hydrogen,C₁₋₆alkyl, cyano, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonylC₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, imidazolyl,haloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, or aradical of formula —O—R¹⁰  (b-1),—S—R¹⁰  (b-2),—N—R¹¹R¹²  (b-3), whereinR¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹, Ar²C₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, a radical or formula -Alk²-OR¹³ or-Alk²-NR¹⁴R¹⁵; R¹¹ is hydrogen, C₁₋₁₂alkyl, Ar¹ or Ar²C₁₋₆alkyl; R¹² ishydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylaminocarbonyl, Ar¹, Ar²C₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, anatural amino acid, Ar¹carbonyl, Ar²C₁₋₆alkylcarbonyl,aminocarbonylcarbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy,C₁₋₆alkyloxy, aminocarbonyl, di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino,C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino, or a radical of formula-Alk²-OR¹³ or -Alk²-NR¹⁴R¹⁵; wherein Alk² is C₁₋₆alkanediyl; R¹³ ishydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, Ar¹ orAr²C₁₋₆alkyl; R¹⁴ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl; R¹⁵ ishydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹ or Ar²C₁₋₆alkyl; R¹⁷ ishydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, Ar¹; R¹⁸ ishydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo; R¹⁹ is hydrogen or C₁₋₆alkyl;Ar¹ is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy, amino,C₁₋₆alkyloxy or halo; and Ar² is phenyl or phenyl substituted withC₁₋₆alkyl, hydroxy, amino, C₁₋₆alkyloxy or halo.
 2. A method accordingto claim 1 wherein X is oxygen, the dotted line represents a bond and R¹is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl or mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl.
 3. A method according to claim 1 wherein R³is hydrogen and R² is halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkyloxy,trihalomethoxy or hydroxyC₁₋₆alkyloxy.
 4. A method according to claim 1wherein R⁸ is hydrogen, hydroxy, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, imidazolyl, or a radicalof formula —NR¹¹R¹² wherein R¹¹ is hydrogen or C₁₋₁₂alkyl and R¹² ishydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl,hydroxy, or a radical of formula —Alk²—OR¹³ wherein R¹³ is hydrogen orC₁₋₆alkyl.
 5. A method according to claim 1 wherein the compound is(±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chloro-phenyl)-1-methyl-2(1H)-quinolinone;or a pharmaceutically acceptable acid addition salt thereof.
 6. A methodaccording to any of claims 1 to 5 wherein the vascular proliferativedisorder is atherosclerosis.
 7. A method according to any of claims 1 to5 wherein the vascular proliferative disorder is restenosis.
 8. A methodaccording to any of claims 1 to 5 wherein the vascular proliferativedisorder is percutaneous transluminal coronary angioplasty restenosis orcoronary artery stent restenosis.
 9. A method of inhibitingproliferation of smooth muscle cells in a warm-blooded animal whichcomprises administering to said warm-blooded animal a prophylacticallyor therapeutically effective amount of a compound as defined in any ofclaims 1 to
 5. 10. A stent covered with a coating material whichcomprises an amount of a compound as defined in any one of claims 1 to 5effective in preventing, treating or reducing smooth muscle cellproliferation.
 11. Use of a compound of formula (I),

a stereoisomeric form thereof, a pharmaceutically acceptable acid orbase addition salt thereof, wherein the dotted line represents anoptional bond; X is oxygen or sulfur; R¹ is hydrogen, C₁₋₁₂alkyl, Ar¹,Ar²C₁₋₆alkyl, quinolinylC₁₋₆alkyl, pyridylC₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl,aminoC₁₋₆alkyl, or a radical of formula -Alk¹-C(═O)—R⁹, -Alk¹-S(O)—R⁹ or-Alk¹-S(O)₂—R⁹, wherein Alk¹is C₁₋₆alkanediyl, R⁹ is hydroxy, C₁₋₆alkyl,C₁₋₆alkyloxy, amino, C₁₋₈alkylamino or C₁₋₈alkylamino substituted withC₁₋₆alkyloxycarbonyl; R², R³ and R¹⁶ each independently are hydrogen,hydroxy, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkyloxy, aminoC₁₋₆alkyloxy, mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹, Ar²C₁₋₆alkyl, Ar²oxy,Ar²C₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, trihalomethyl,trihalomethoxy, C₂₋₆alkenyl, 4,4-dimethyloxazolyl; or formula when onadjacent positions R² and R³ taken together may form a bivalent radicalof—O—CH₂—O—  (a-1)—O—CH₂—CH₂—O—  (a-2),—O—CH═CH—  (a-3),—O—CH₂—CH₂—  (a-4),—O—CH₂—CH₂—CH₂—  (a-5),or—CH═CH—CH═CH—  (a-6); R⁴ and R⁵ each independently are hydrogen, halo,Ar¹, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl , C₁₋₆alkyloxy,C₁₋₆alkylthio, amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylS(O)C₁₋₆alkyl or C₁₋₆alkylS(O)₂C₁₋₆alkyl; R⁶ and R⁷ eachindependently are hydrogen, halo, cyano, C ₁₋₆alkyl, C₁₋₆alkyloxy,Ar²oxy, trihalomethyl, C₁₋₆alkylthio, di(C₁₋₆alkyl)amino, or when onadjacent positions R⁶ and R⁷ taken together may form a bivalent radicalof formula —O—CH₂—O—  (c-1), or—CH═CH—CH═CH—  (c-2); R⁸ is hydrogen,C₁₋₆alkyl, cyano, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonylC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, imidazolyl,haloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, or aradical of formula —O—R¹⁰  (b-1),—S—R¹⁰  (b-2),—N—R¹¹R¹²   (b-3),wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹,Ar²C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁ ₋ ₆alkyl, a radical or formula-Alk²-OR¹³ or -Alk²-NR¹⁴R¹⁵; R¹¹ is hydrogen, C₁₋₁₂alkyl, Ar¹ orAr²C₁₋₆alkyl; R¹² is hydrogen, C₁₋₆alkyl, C₁₋₁₆alkylcarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylaminocarbonyl, Ar¹, Ar²C₁₋₆alkyl,C₁₋₆alkylcarbonylC₁₋₆alkyl, a natural amino acid, Ar¹carbonyl,Ar²C₁₋₆alkylcarbonyl, aminocarbonylcarbonyl,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy, aminocarbonyl,di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino, C₁₋₆alkylamino,C₁₋₆alkylcarbonylamino, or a radical of formula -Alk²-OR¹³ or-Alk²-NR¹⁴R¹⁵; wherein Alk² is C₁₋₆alkanediyl; R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl; R¹⁴is hydrogen, C₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl; R¹⁵ is hydrogen, C₁₋₆alkyl,C₁₋₆alkylcarbonyl, Ar¹ or Ar²C₁₋₆alkyl; R¹⁷ is hydrogen, halo, cyano,C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, Ar¹; R¹⁸ is hydrogen, C₁₋₆alkyl,C₁₋₆alkyloxy or halo; R¹⁹ is hydrogen or C₁₋₆alkyl; Ar¹ is phenyl orphenyl substituted with C₁₋₆alkyl, hydroxy, amino, C₁₋₆alkyloxy or halo;and Ar² is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy, amino,C₁₋₆alkyloxy or halo; for the manufacture of a medicament to prevent orto treat vascular proliferative disorders.
 12. Use according to claim 11of a compound wherein X is oxygen, the dotted line represents a bond andR¹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl or mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl.
 13. Use according to any of claims 11 to 12of a compound wherein R³ is hydrogen and R² is halo, C₁₋₆alkyl,C₂₋₆alkenyl, C₁₋₆alkyloxy, trihalomethoxy or hydroxyC₁₋₆alkyloxy. 14.Use according to any of claims 11 to 13 of a compound wherein R⁸ ishydrogen, hydroxy, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, imidazolyl, or a radical of formula—NR¹¹R¹² wherein R¹¹ is hydrogen or C₁₋₁₂alkyl and R¹² is hydrogen,C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, or aradical of formula -Alk²-OR¹³ wherein R¹³ is hydrogen or C₁₋₆alkyl. 15.Use according to claim 11 of wherein the compound is(±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chloro-phenyl)-1-methyl-2(1H)-quinolinone; or a pharmaceutically acceptable acid addition saltthereof.
 16. Use according to any of claims 11 to 15 wherein thevascular proliferative disorder is atherosclerosis.
 17. Use according toany of claims 11 to 15 wherein the vascular proliferative disorder isrestenosis.
 18. Use according to any of claims 11 to 15 wherein thevascular proliferative disorder is percutaneous transluminal coronaryangioplasty restenosis or coronary artery stent restenosis.
 19. Use of acompound of formula (I) as defined in any of claims 11 to 15, for themanufacture of a medicament for the inhibition of smooth muscle cellproliferation.